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From the Department of Pathology and Laboratory Medicine, University Hospital Groningen, Groningen, The Netherlands
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Abstract |
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Introduction |
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The second characteristic feature of Hodgkin's lymphoma is the presence of CD4-positive T lymphocytes that strongly bind to the R-S cells and have phenotypic features of Th2 helper T cells.2,3 One of the intriguing questions is what causes the influx of T lymphocytes into the involved tissues. It has been hypothesized that R-S cells secrete potent cytokines that stimulate their own growth, allow them to evade immune surveillance, and cause the systemic symptoms of Hodgkin's disease.4,5
To gain insight into the genes that are expressed in R-S cells as opposed to normal EBV-transformed B cells, we applied serial analysis of gene expression (SAGE).6 This technique allows the construction of a comprehensive expression profile and results in the quantitation of expression levels of the corresponding genes. We analyzed a Hodgkin's lymphoma-derived cell line (L428) and an EBV-transformed lymphoblastoid B-cell line (RAY) for comparison. Differentially expressed genes were further analyzed in tissues involved by Hodgkin's lymphoma and some related lymphoma types.
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Materials and Methods |
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The L428, L540, L591, and L1236 Hodgkin's lymphoma-derived cell lines7,8 were made available to us by Dr. Volker Diehl and co-workers (Cologne, Germany). The RAY and POP lymphoblastoid cell lines were initiated by transforming peripheral blood B cells with EBV. Large-B-cell non-Hodgkin lymphoma cell lines VER and Rose were established in our laboratory (unpublished data). VER was derived from a large-cell B-cell lymphoma with t(8;14) secondary to Hodgkin's lymphoma. Rose was derived from a large-cell B-cell lymphoma with t(14;18) derived from a transformed follicular lymphoma. Anaplastic large-cell lymphoma cell line KARPAS 299 was obtained from American Type Culture Collection, Rockville, MD.9
Tissues
Frozen tissue specimens and cell suspensions of lymph nodes involved by Hodgkin's and non-Hodgkin's lymphomas came from the tissue bank of the Department of Pathology. We randomly selected eight cases of nodular sclerosis (NS), four cases of mixed cellularity (MC), and six cases of nodular lymphocyte predominance (NLP) subtype. In addition, four cases of anaplastic large-cell lymphoma (ALCL) (T/0), six cases of large-B-cell lymphoma with CD30 positivity, and five T-cell-rich B-cell lymphomas (TCRBCL) were studied. As control tissues we included a lymph node with dermatopathic lymphadenopathy, a lymph node with follicular and diffuse hyperplasia, and a case with progressively transformed germinal centers.
Purification of R-S Cells
A cell suspension of one of the lymph nodes involved by NS Hodgkin's lymphoma was incubated with anti-CD30 (Mab BerH2, gift of Dr. Harald Stein, Berlin, Germany), and the CD30-positive R-S cells were isolated by binding to sheep anti-mouse Ig-labeled magnetic beads (Dynal, Oslo, Norway). The cells labeled with magnetic beads were isolated with the equipment provided by the manufacturer. The nonbound cells were saved as the depleted population. The bound cells were washed three times to remove the contaminating CD30-negative cells and kept as the enriched cells. The efficiency of the purification was checked in cytospins from the starting lymphoma cell population, the enriched CD30-positive cells, and the depleted cell population. RNA was isolated from the enriched CD30-positive R-S cell population and from the CD30-depleted cell population.
SAGE Procedure
A detailed protocol for the SAGE procedure and the SAGE300
computer program (version 3.03) used for the analysis of the tags were
kindly provided by Dr. Kinzler (Johns Hopkins Oncology Center,
Baltimore, MD).6
mRNA was isolated from the L428 and RAY
cell lines (starting from 1 x 107
to 2 x
107
cells), converted into double-stranded (ds)-cDNA
(TimeSaver cDNA synthesis kit, Amersham Pharmacia Biotech, Rainham,
UK), and digested with NlaIII. The 3'-primed ds-cDNA
fragments were isolated and ligated to a linker. A second restriction
enzyme digest with BsmFI was performed, resulting in 50-bp
fragments containing the linker sequences and 10 to 12 gene-specific
bases that originate downstream from the NlaIII restriction
site (the so-called tags). After filling in of the sticky ends, the
blunt-ended DNA fragments were pooled and ligated (resulting in the
so-called ditags). Large-scale amplification of the ditags then gave
polymerase chain reaction (PCR) products of ~100 bp consisting of two
10- to 12-nucleotide fragments from two different genes flanked by the
linker sequences. These PCR products were digested with
NlaIII to purify the gene-specific sequences from the
linkers. The 24- to 28-bp fragments containing two gene-specific
sequences were ligated overnight to obtain concatemers. The concatamers
were cloned in the pUC18 vector (digested with SphI) and
transformed to Escherichia coli DH5-
cells (Gibco BRL,
Paisley, UK). The clones were sequenced on an automated sequencer (ALF,
Amersham Pharmacia Biotech). The sequence files were analyzed with the
SAGE300 computer program.6
The tag sequences were used to
screen for homologies with genes present in the GenBank. In case a gene
corresponded to a tag, the 15th base that usually is present in the
ditag sequence was used to confirm the homology.
RT-PCR on Hodgkin Lymphoma Tissues for TARC,CCR4, and CCR8
Total RNA was isolated with Trizol (Gibco BRL, Gaithersburg, MD)
from cell suspension and from cryostat tissue sections. The cDNA
syntheses was primed with oligo(dT) using the protocol provided by the
manufacturer (MBI Fermentas, St. Leon-Rot, Germany). Primer
sequences used for the amplification are listed in Table 1
. PCR for all primer sets was performed
with 1 U of Taq polymerase (Pharmacia Biotech) and the
reaction buffer provided by the manufacturer. The PCR program consisted
of 33 cycles with a denaturation step of 30 seconds at 94°C, an
annealing step of 45 seconds at 57°C, and an extension step of 45
seconds at 72°C. The first denaturation step lasted for 5 minutes,
and the final extension step lasted for 7 minutes.
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The RT-PCR products were subcloned in the pCRII-TOPO vector (Invitrogen, Carlsbad, NM). Digoxigenin (DIG)-labeled RNA probes were made with the DIG RNA labeling kit (Sp6/T7) (Boehringer Mannheim, Mannheim, Germany). In situ hybridization (ISH) was performed on routinely fixed paraffin-embedded tissue sections using standard laboratory protocols.
Immunohistochemistry
Immunohistochemical staining was performed with an affinity-purified goat anti-human TARC antibody (R&D Systems, Minneapolis, MN) on paraffin tissue sections after heat-induced antigen retrieval. Peroxidase-labeled rabbit anti-goat antibody (DAKO, Copenhagen, Denmark) followed by peroxidase enzyme staining with diaminobenzidine and H2O2 were used to visualize the TARC-positive cells. Paraffin sections of 12 cases of NS, 4 cases of MC, and 6 cases of NLP Hodgkin's lymphoma, 7 lymph nodes with follicular and/or diffuse hyperplasia, 1 lymph node with progressively transformed germinal centers, 20 common B-cell non-Hodgkin lymphomas, 6 anaplastic large-cell B-cell lymphomas, 4 T/0 anaplastic large-cell lymphomas, and 5 T-cell-rich B-cell lymphomas were stained.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.
For RAY, 417 of the tags occurred only once, whereas the remaining 57
tags occurred up to 25 times. Homology screening of the L428 tags to
the known human sequences (release 107.0 of the GenBank) resulted in
the identification of the corresponding genes for 247 of the tags.
Among these genes we detected housekeeping genes, such as
GAPDH and ß-actin, and a high number of
ribosomal genes, of which 34 of 49 were present in both libraries. In
addition, we also identified a tag corresponding to CD30, a
known R-S cell marker, and Fascin for which a high
expression has been reported in Hodgkin's lymphoma.10
Screening of the remaining tags for homology to human EST sequences
resulted in the identification of a corresponding sequence for 243
(Table 2)
. An overview of the most frequently occurring L428-specific
tags is given in Table 3
. One of the tags
corresponded to the T-cell-directed CC chemokine TARC
(thymus and activation regulated chemokine)11
(GenBank
accession number D43767) and was detected nine times in L428 (0.9%)
and not in RAY. Primers specific for TARC were selected from
the nucleotide sequence and used for the amplification of the
TARC mRNA in L428, RAY, and some other Hodgkin's and
non-Hodgkin's lymphoma cell lines (Figure 1)
. TARC was expressed only in
the Hodgkin's lymphoma-derived cell lines L428, L491, L540, and L1236
and not in the lymphoblastoid B-cell lines RAY and POP and
non-Hodgkin's lymphoma-derived cell lines (Table 4)
. To determine whether the expression
of TARC was consistently present in and specific for
Hodgkin's lymphoma we analyzed a number of other Hodgkin's and
non-Hodgkin's lymphoma tissue and cell suspension samples (Figure 2)
. TARC expression was found
in the eight tissues with NS and in the four with MC Hodgkin's
lymphoma (Table 5)
. Hyperplastic tonsils
and lymph nodes were negative with the exception of a case of
dermatopathic lymphadenopathy that had a high content of Langerhans'
and interdigitating reticulum cells.
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The findings support that the TARC signals indeed derive
from the R-S cells.
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. Other cell types were
negative, and no signal was obtained with the control sense probe.
Immunohistochemical staining for the TARC protein on paraffin sections
resulted in a very strong signal in the cytoplasm of R-S cells with a
diffuse or a distinct paranuclear dot-like staining pattern (Figure 4C)
. The 12 NS-type cases stained stronger than the 4 MC-type cases,
whereas all 6 cases of NLP type were negative. The only other staining
for TARC was found in interdigitating cells in reactive lymph nodes and
was much weaker.
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We also analyzed the samples for expression of CCR4 and
CCR8,12-14
which are known to be specific
receptors for TARC. All Hodgkin's and non-Hodgkin's lymphoma cell
line and tissue samples were found to be positive by RT-PCR (Figures 1 and 2
; Tables 4 and 5
). In normal peripheral blood cells, expression of
CCR4 could be detected only after a 24-hour stimulation with
PHA. In situ hybridization with an antisense probe for
CCR4 showed a small dot-like signal in the cytoplasm of a
high proportion of the lymphocytes surrounding the R-S cells (Figure 4B)
. No CCR4 signal was found in the R-S cells in these
tissue sections, and the sense probe also showed no positive signal.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Binding assays of the known CC chemokine receptors (CCR 1 to 5) have shown that TARC binds to the CCR4 receptor with high affinity, and expression of CCR4 has been reported for T-cell lines and activated peripheral blood T cells.12 Analysis of T-cell clones and polarized Th1 and Th2 cells has indicated that expression of CCR4 is specific for activated Th2 cells whereas CCR5 is expressed on Th1 cells.13-15 More recently, TARC was also shown to bind to CCR8.16 Expression of CCR8 has been reported for interleukin-2-treated T lymphocytes.17 RT-PCR analysis revealed the presence of CCR4 mRNA in all Hodgkin's lymphoma samples and also in the Hodgkin's lymphoma cell lines analyzed. By RNA in situ hybridization, CCR4 mRNA was found only in the T cells surrounding the R-S cells and not in the R-S cells. The presence of CCR4 in the Hodgkin's and non-Hodgkin's lymphoma cell lines may be an artifact as the growth of these cells in vitro is an unusual event that may require or induce expression of certain genes.
The characteristics of the T cells directly surrounding the R-S cells are consistent with an activated Th2-like phenotype.2,3 The high expression of TARC in the R-S cells and the expression of CCR4 in the surrounding T cells suggest that the CC chemokine TARC may be responsible for the attraction of Th2 lymphocytes into the tissues involved by Hodgkin's lymphoma. Migration and binding of lymphocytes to tumor cells in vivo and in vitro, the so-called lymphocyte rosetting phenomenon, occurs around R-S cells and Hodgkin's but not non-Hodgkin's lymphoma cell lines and correlates with TARC expression.
The lymphocytic & histiocytic (L&H)-type R-S cells of the NLP subtype of Hodgkin's lymphoma do not express the TARC chemokine. This presents yet another distinction from the other subtypes. The L&H cells have a more typical germinal center B-cell phenotype with somatic hypermutations but no crippling mutations1,18,19 and frequently express membrane or cytoplasmic immunoglobulin.20 The lymphocytic infiltrate in NLP Hodgkin's lymphoma also differs and consists of predominantly small B lymphocytes with rosettes around the L&H cells of CD57-positive CD4 cells that are normally found in the light zones of germinal centers.21 The presence of a similar lymphocyte population in progressively transformed germinal centers, a potential precursor lesion of NLP Hodgkin's lymphoma in which L&H cells are lacking, suggests that the L&H cells are not responsible for the influx of the T lymphocytes in this subset.
The tumor cells of ALCL have several morphological and immunophenotypic similarities to R-S cells, but all cases of T/0 type, whether ALK positive or negative, were found to be TARC negative. Cases of large B-cell lymphoma with anaplastic morphology and/or CD30 positivity were also negative. It will be of interest to see how so-called cases of Hodgkin's-like ALCL22 will segregate and whether expression of TARC or other dendritic cell characteristics is clinically relevant.
Another lymphoma with similarities to Hodgkin's lymphoma is TCRBCL, which comprises a group of non-Hodgkin lymphomas characterized by neoplastic large B cells and a high content of T lymphocytes. In two of five cases, expression of TARC was detected. This indicates that in some cases of this type of non-Hodgkin's lymphoma, TARC may be involved in the lymphocyte attraction in a similar way as in Hodgkin's lymphoma and suggests that also other chemokines may be involved.
TARC expression is normally restricted to cells that have
antigen-presenting functions, such as the interdigitating cells in the
paracortex of lymph nodes. These cells have much weaker expression than
the R-S cells. The mechanisms that lead to the very high expression of
TARC in R-S cells are not known. Many cytokines, including
interleukin (IL)-1, IL-5, IL-6, IL-9, IL-10, and transforming growth
factor-ß are produced by R-S cells,4
and it is suspected
that constitutive nuclear expression of nuclear factor (NF)-
B is
responsible for this phenomenon.23,24
NF-B activation
caused by the HTLV-1-encoded transactivator Tax can lead to the
expression of several chemokines.25
It is therefore
possible that the up-regulation of TARC also results from NF-B
activation.
The significance of a high expression of TARC by R-S cells is that TARC may cause an influx of activated Th2-type lymphocytes and thereby contribute to the characteristic lymphocytic infiltrate of Hodgkin's lymphoma. The upside of this phenomenon is that it may provide an early warning of the disease by leading to an exaggerated swelling of the node while still relatively few tumor cells are present. The downside is that a Th2-type response in combination with immunosuppressive factors such as IL-10 and transforming growth factor-ß may prevent an effective immune response against the R-S cells.
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Footnotes |
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Accepted for publication March 12, 1999.
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U. E. Hopken, H.-D. Foss, D. Meyer, M. Hinz, K. Leder, H. Stein, and M. Lipp Up-regulation of the chemokine receptor CCR7 in classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs Blood, February 15, 2002; 99(4): 1109 - 1116. [Abstract] [Full Text] [PDF]
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D. Aldinucci, D. Poletto, A. Gloghini, P. Nanni, M. Degan, T. Perin, P. Ceolin, F. M. Rossi, V. Gattei, A. Carbone, et al. Expression of Functional Interleukin-3 Receptors on Hodgkin and Reed-Sternberg Cells Am. J. Pathol., February 1, 2002; 160(2): 585 - 596. [Abstract] [Full Text] [PDF]
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E. Oelmann, H. Herbst, M. Zuhlsdorf, O. Albrecht, A. Nolte, C. Schmitmann, O. Manzke, V. Diehl, H. Stein, and W. E. Berdel Tissue inhibitor of metalloproteinases 1 is an autocrine and paracrine survival factor, with additional immune-regulatory functions, expressed by Hodgkin/Reed-Sternberg cells Blood, January 1, 2002; 99(1): 258 - 267. [Abstract] [Full Text] [PDF]
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P. Fiumara, F. Cabanillas, and A. Younes Interleukin-13 levels in serum from patients with Hodgkin disease and healthy volunteers Blood, November 1, 2001; 98(9): 2877 - 2878. [Full Text] [PDF]
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A. L. N. Chapman, A. B. Rickinson, W. A. Thomas, R. F. Jarrett, J. Crocker, and S. P. Lee Epstein-Barr Virus-specific Cytotoxic T Lymphocyte Responses in the Blood and Tumor Site of Hodgkin's Disease Patients: Implications for a T-cell-based Therapy Cancer Res., August 1, 2001; 61(16): 6219 - 6226. [Abstract] [Full Text] [PDF]
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 M. Cecilia Berin, L. Eckmann, D. H. Broide, and M. F. Kagnoff Regulated Production of the T Helper 2-Type T-Cell Chemoattractant TARC by Human Bronchial Epithelial Cells In Vitro and in Human Lung Xenografts Am. J. Respir. Cell Mol. Biol., April 1, 2001; 24(4): 382 - 389. [Abstract] [Full Text]
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C. Buri, M. Korner, P. Scharli, D. Cefai, M. Uguccioni, C. Mueller, J. A. Laissue, and L. Mazzucchelli CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease Blood, March 15, 2001; 97(6): 1543 - 1548. [Abstract] [Full Text] [PDF]
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E. Kuroda, T. Sugiura, K. Okada, K. Zeki, and U. Yamashita Prostaglandin E2 Up-Regulates Macrophage-Derived Chemokine Production but Suppresses IFN-Inducible Protein-10 Production by APC J. Immunol., February 1, 2001; 166(3): 1650 - 1658. [Abstract] [Full Text] [PDF]
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R. Kuppers, A. Brauninger, M. Muschen, V. Distler, M.-L. Hansmann, and K. Rajewsky Evidence that Hodgkin and Reed-Sternberg cells in Hodgkin disease do not represent cell fusions Blood, February 1, 2001; 97(3): 818 - 821. [Abstract] [Full Text] [PDF]
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B. F. Skinnider, A. J. Elia, R. D. Gascoyne, L. H. Trumper, F. von Bonin, U. Kapp, B. Patterson, B. E. Snow, and T. W. Mak Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma Blood, January 1, 2001; 97(1): 250 - 255. [Abstract] [Full Text] [PDF]
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 R. Chrast, H. S. Scott, M. P. Papasavvas, C. Rossier, E. S. Antonarakis, C. Barras, M. T. Davisson, C. Schmidt, X. Estivill, M. Dierssen, et al. The Mouse Brain Transcriptome by SAGE: Differences in Gene Expression between P30 Brains of the Partial Trisomy 16 Mouse Model of Down Syndrome (Ts65Dn) and Normals Genome Res., December 1, 2000; 10(12): 2006 - 2021. [Abstract] [Full Text]
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 G Niedobitek Epstein-Barr virus infection in the pathogenesis of nasopharyngeal carcinoma Mol. Pathol., October 1, 2000; 53(5): 248 - 254. [Abstract] [Full Text]
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D. F. Dukers, P. Meij, M. B. H. J. Vervoort, W. Vos, R. J. Scheper, C. J. L. M. Meijer, E. Bloemena, and J. M. Middeldorp Direct Immunosuppressive Effects of EBV-Encoded Latent Membrane Protein 1 J. Immunol., July 15, 2000; 165(2): 663 - 670. [Abstract] [Full Text] [PDF]
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K. Willenbrock, A. Roers, B. Blohbaum, K. Rajewsky, and M.-L. Hansmann CD8+ T Cells in Hodgkin's Disease Tumor Tissue Are a Polyclonal Population with Limited Clonal Expansion but Little Evidence of Selection by Antigen Am. J. Pathol., July 1, 2000; 157(1): 171 - 175. [Abstract] [Full Text] [PDF]
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J. T. Stine, C. Wood, M. Hill, A. Epp, C. J. Raport, V. L. Schweickart, Y. Endo, T. Sasaki, G. Simmons, C. Boshoff, et al. KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells Blood, February 15, 2000; 95(4): 1151 - 1157. [Abstract] [Full Text] [PDF]
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M. Muschen, K. Rajewsky, A. Brauninger, A. S. Baur, J. J. Oudejans, A. Roers, M.-L. Hansmann, and R. Kuppers Rare Occurrence of Classical Hodgkin's Disease as a T Cell Lymphoma J. Exp. Med., January 17, 2000; 191(2): 387 - 394. [Abstract] [Full Text] [PDF]
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 R. Kuppers, U. Klein, M.-L. Hansmann, and K. Rajewsky Cellular Origin of Human B-Cell Lymphomas N. Engl. J. Med., November 11, 1999; 341(20): 1520 - 1529. [Full Text] [PDF]
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